Antimetabolites in the treatment of advanced pleural mesothelioma: a network meta-analysis of randomized clinical trials

Our plain-English summary of Antimetabolites in the treatment of advanced pleural mesothelioma: a network meta-analysis of randomized clinical trials, by D. Tassinari, C. Cherubini, E. Tamburini, et al (Journal of Chemotherapy, 2017).

The study

• Authors: D. Tassinari, C. Cherubini, E. Tamburini, F. Drudi, M. Papi, M. Fantini, L. Lazzari-Agli, S. Sartori
• Journal: Journal of Chemotherapy
• Published: 2017;29(6):365-371
• Read it: PubMed · Publisher

Abstract

An indirect comparison of cisplatin-pemetrexed (CP) and cisplatin-raltitrexed (CR) was performed. The Odds Ratios of 10, 15 and 20 month survival rate and response rate were assumed as indexes of efficacy; the Odds Ratio of grade III-IV side effects, and the absolute risk of overall, hematologic and non-hematologic toxicity, were assumed as indexes of safety. The outcomes of 352 patients were analysed. The Odds Ratios and 95% Confidence Interval (95% CI) of 10, 15 and 20 months survival rate and response rate were 1.2 (95% CI 0.65-2.24, p = 0.559), 1.02 (95% CI 0.49-2.12, p = 0.953), 1.13 (95% CI 0.44-2.91, p = 0.805) and 0.56 (95% CI 0.26-1.21, p = 0.141), respectively. An absolute increased risk of grade III-IV side effects was observed for CP: 6% (95% CI 3-9%, p < 0.001), 9% (95% CI 2-16%, p = 0.008) and 3% (95% CI 0-5%, p = 0.035) for overall, hematological and non-hematological toxicity. CP and CR can be considered comparable in terms of efficacy in the treatment of metastatic pleural mesothelioma, with a modest increased risk of grade III-IV side effects for CP.

In plain English

This network meta-analysis indirectly compared two chemotherapy combinations for advanced pleural mesothelioma: cisplatin with pemetrexed and cisplatin with raltitrexed. The authors treated no patients; they took data from two earlier randomized trials, by Vogelzang et al. and Van Meerbeek et al., each comparing one combination with cisplatin alone. Together these trials enrolled 698 patients. Of these, 226 had received cisplatin-pemetrexed and 126 cisplatin-raltitrexed. The comparison found no statistically significant difference between the two combinations in survival at 10, 15 or 20 months, or in response rate. Cisplatin-pemetrexed carried a higher absolute risk of severe (grade III–IV) side effects. In the full trial populations the increase was 6 percentage points (95% CI 3 to 9) for any side effect and 9 percentage points (95% CI 2 to 16) for blood-related side effects. The authors judged this difference negligible in clinical terms. They concluded that the two combinations can be considered comparable in efficacy. They cautioned that indirect comparisons remain methodologically unsettled, that no significant difference does not mean equivalence, and that the analysis may have lacked power.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Network meta-analysis (indirect comparison) using data from two published randomized clinical trials
• Who was studied: Patients with pleural mesothelioma who were fit for chemotherapy and had not had chemotherapy before, enrolled in two randomized trials (Vogelzang et al., 448 patients; Van Meerbeek et al., 250 patients; 698 in total). Of these, 226 received cisplatin-pemetrexed, 126 cisplatin-raltitrexed and 346 cisplatin alone. The article does not say where or when the trials were run.
• Exposure: Not an asbestos exposure study. The treatments compared were first-line chemotherapy with cisplatin plus pemetrexed versus cisplatin plus raltitrexed. Data for the pemetrexed group were analysed both for the whole group and for the subgroup given full folinic acid and vitamin B12 supplementation.
• Main results:
  • Whole trial populations, cisplatin-pemetrexed compared indirectly with cisplatin-raltitrexed, odds ratios for being alive: at 10 months 1.20 (95% CI 0.65–2.24, p = 0.559); at 15 months 1.02 (95% CI 0.49–2.12, p = 0.954); at 20 months 1.13 (95% CI 0.44–2.91, p = 0.805). None was statistically significant.
  • Whole trial populations, cisplatin-pemetrexed compared indirectly with cisplatin-raltitrexed: odds ratio for response rate 0.56 (95% CI 0.26–1.21, p = 0.141), not statistically significant.
  • Using only the pemetrexed patients with full vitamin supplementation: odds ratios for being alive at 10, 15 and 20 months were 1.17 (95% CI 0.60–2.27, p = 0.640), 0.92 (95% CI 0.41–2.06, p = 0.832) and 1.14 (95% CI 0.36–3.66, p = 0.826). The odds ratio for response rate was 0.55 (95% CI 0.28–1.08, p = 0.081).
  • Absolute risk of any grade III–IV side effect was higher with cisplatin-pemetrexed by 6 percentage points (95% CI 3 to 9, p less than 0.001) in the whole trial population (intention to treat).
  • In the pemetrexed patients with full vitamin supplementation, the absolute risk of any grade III–IV side effect was higher by 3 percentage points (95% CI 0 to 6, p = 0.022).
  • Absolute risk of grade III–IV hematological (blood-related) side effects was higher with cisplatin-pemetrexed by 9 percentage points (95% CI 2 to 16, p = 0.008) in the whole population, and by 7 percentage points (95% CI 1 to 13, p = 0.024) in patients with full vitamin supplementation.
  • Absolute risk of grade III–IV non-hematological side effects was higher with cisplatin-pemetrexed by 3 percentage points (95% CI 0 to 5, p = 0.035) in the whole population. In patients with vitamin supplementation the difference was 1 percentage point (95% CI minus 1 to 4, p = 0.288), not a significant increase.
  • The authors judged the difference in side effects statistically significant but clinically negligible, and considered the safety of the two regimens quite similar.
  • The cisplatin-alone groups of the two trials differed significantly in 15-month survival (14.4% in the Vogelzang trial vs 25% in the Van Meerbeek trial, p = 0.0144). No significant difference was seen at 10 and 20 months.
• The authors' conclusion: The authors concluded that cisplatin-pemetrexed and cisplatin-raltitrexed can be considered comparable in efficacy for metastatic pleural mesothelioma, with a modest increased risk of grade III–IV side effects for cisplatin-pemetrexed.
• Limitations the authors state:
  • The methodological value of indirect comparisons still needs definitive confirmation, so the data must be interpreted with caution.
  • Finding no significant difference between two treatments does not mean they are equivalent.
  • The comparisons may not have had the statistical power to detect a significant difference in the main outcomes.
  • This method is not a synthesis of the randomized trials; it generates clinical hypotheses through indirect investigation.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Meta-Analysis, Clinical Trial, Cisplatin, Pemetrexed (Alimta), Raltitrexed, Odds Ratio, confidence interval.

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• Randomized phase II trial of pemetrexed/cisplatin with or without CBP501 in patients with advanced malignant pleural mesothelioma — L.M. Krug, A.J. Wozniak, et al. (2014)
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